Monogenic obesity in humans (#84)
Obesity has reached epidemic proportions worldwide. Genetic and environmental factors, individually and through gene-environment and gene-gene interactions, play a major role in determining fat mass in humans. Genome-wide association studies have identified common gene variants associated with moderate alterations in body weight. In contrast, single-gene or monogenic obesity disorders result in severe early-onset obesity. Mutations in genes encoding key regulators of appetite in the hypothalamus, including leptin, the leptin receptor, pro-opiomelanocortin (POMC), prohormone convertase 1/3 and the melanocortin 4 receptor (MC4R), have been identified in humans with severe, early-onset obesity. Most of these disorders are rare and inherited recessively, with the exception of MC4R deficiency, an autosomal dominant disorder accounting for 3-6% of severe obesity cases. A striking feature of all monogenic disorders is marked hyperphagia, with little, if any measurable defect in energy expenditure. Humans with mutations in leptin and leptin receptor are also characterised by T-cell hyporesponsiveness and neuroendocrine dysfunction. POMC deficiency results in early-onset obesity, red hair and adrenal insufficiency. MC4R deficiency is characterised by increased fat and lean body mass, disproportionate hyperinsulinaemia (up to age 20 years), tall stature, increased bone density, lower-than-expected pulse rate and relative protection from the development of hypertension. The study of humans with these disorders will shed light on the importance of the leptin-melanocortin pathway in determining human adiposity and will also allow the development of more specific and better-targeted treatment options. Indeed, treatment of leptin-deficient humans with subcutaneous rh-leptin results in significant weight loss, due entirely to loss of fat (as opposed to obligatory loss of both fat and muscle in diet-induced weight loss), a consequence of a significant reduction in hyperphagia. MC4R agonists are currently in development, but potential adverse cardiovascular effects, such as tachycardia and hypertension, need to be addressed.